Chronic pain after surgery has garnered considerable attention, but it is but one facet of chronic dysfunction after surgery important to patients. Othes include cognitive and physical dysfunction, fear of pain and movement, and impulsivity, which is tied to risk of prescription opioid misuse. These problems occur in a large minority of patients (10-40%), depending on the outcome measure, after total knee arthroplasty (TKA). This P01 seeks to address barriers to progress in understanding, preventing, and treating chronic pain and disability after surgery which are so fundamental that they cannot be meaningfully impacted by individual investigators acting in isolation. 1) Both preclinical and clinical research is stymid by use of point incidences of dysfunction at arbitrary times as primary outcomes; we show the increased power of modeling time course of recovery in individual animals and humans after surgery and its utility to examine interventions and mechanisms. 2) Recovery is typically examined in one domain: we examine several patient-centered domains after TKA and their mechanisms in animals. 3) Recovery after surgery in patients is predicted by preoperative cognitive-affective (C-A) state by unknown mechanisms and preclinical research studies recovery in normal animals only: we provide a unifying, mechanistic, and clinically actionable hypothesis relating C-A state and locus coeruleus (LC) function and use it to test novel targeting of therapies to speed recovery after TKA. Over the past 4 years this group of independently funded investigators has worked together to generate new animal models, develop concepts, and demonstrate feasibility of addressing each of these critical barriers. As supported by innovative Administrative and Research Cores, this P01 as a whole will have a major impact in the field by examining a central hypothesis and 3 cohesive, interactive aims: 1. CENTRAL HYPOTHESIS: Activity of the LC at the time of and in response to surgical injury is a key determinant of speed of recovery across pain and other patient-centered domains 2. PROJECT 1: LC ? spinal cord signaling is essential to normal recovery from hypersensitivity and disability after surgery and is disrupted by experimentally induced increased tonic LC activity 3. PROJECT 2: LC ? spinal cord, signaling to supraspinal regions is essential to recovery from pain, impulsivity, and distraction after surgery and is disturbed by pre-surgery increased tonic LC activity 4. PROJECT 3: LC tonic activity interacts with a catastrophizing ? optimism cognitive style continuum to explain novel variance in time course of recovery across multiple patient domains and identifies patients who will benefit from or be harmed by preventative gabapentin treatment